The underdog coronavirus vaccines that the world will need if front runners stumble

A woman receives a vaccination.

There are more than 175 COVID-19 vaccines in development, but only a handful are in final-stage clinical trials.Credit: Joe Raedle/Getty

When it comes to developing vaccines, Peter Palese is no slouch. A virologist at Icahn School of Medicine at Mount Sinai in New York City, he pioneered genetics techniques that are used to make some of the billions of influenza vaccine doses produced annually, and his team has won millions of dollars to develop a universal flu jab.

Palese is developing a COVID-19 vaccine, too. It consists of a bird virus genetically modified to make a protein found on the surface of the SARS-CoV-2 coronavirus. The vaccine fully protects mice from an experimental model of COVID-191, according to a recent preprint (the research has not yet been peer reviewed). It also grows in chicken eggs, like most flu vaccines, so manufacturing could be ramped up using tried-and-tested technology.

Despite its potential, Palese’s vaccine has struggled to gain the attention and funding needed to progress to human trials. “We thought this would be the best thing after sliced bread, and people would break down our doors to get it. That’s not the case. We are very disappointed,” he says.


As leading pharmaceutical and biotechnology companies speed their COVID-19 vaccines through clinical trials and eye up fast-track regulatory authorization, dozens of underdog vaccines such as Palese’s have stalled, or are advancing along a slower, more conventional path.

Scientists acknowledge that it would be a waste of resources to take every candidate to clinical trials. But they argue that it’s essential to have a diverse selection of COVID-19 vaccines in development. Early favourites could fail, confer only partial protection or work poorly in certain age groups; high costs and other barriers might make some of the front runners unsuitable for wide-scale deployment in lower-income countries.

“Everyone is rooting for them to succeed beyond anyone’s expectation, but it’s prudent to think about what happens if they don’t,” says Dave O’Connor, a virologist at the University of Wisconsin–Madison. “We need to make sure we have back-up plans — and back-up plans to those back-up plans.”

Dozens of candidates

There are more than 320 COVID-19 vaccines in development, according to a recent tally by the Coalition for Epidemic Preparedness Innovation (CEPI) in Oslo, a fund created to finance and coordinate vaccines for outbreaks. Most of these are in the early stages of preclinical development; several dozen are in clinical trials, and only a handful have begun final-phase tests for efficacy. “Everybody and their mother has a vaccine. My dogs have two vaccines,” says one scientist working on a leading candidate. Although on the face of it this is good news, it also presents challenges. One is determining which candidates should move forward to costly clinical trials: running even a small study to test safety and dosing is beyond the reach of most academic groups, and smaller teams face an uphill struggle to get their candidates noticed.

In some cases, the breakneck pace of COVID-19 vaccine efforts has created openings for academic groups. One of the leading candidates is being developed by the University of Oxford, UK, and drug company AstraZeneca (trial enrolment was paused after a participant developed a serious health problem, the company said on 8 September). The vaccine is based on a kind of chimpanzee cold virus, called an adenovirus, that has been used for experimental vaccines against Ebola, malaria and other diseases, allowing Oxford vaccinologists to quickly adapt the platform to a COVID-19 vaccine. Another technology comprises RNA instructions for a coronavirus protein, and two front-runner vaccines are being developed by firms with expertise in that platform.


But neither technology has yet produced licensed vaccines, and there is no guarantee that the candidates will generate strong immunity against the coronavirus, says Michael Diamond, a viral immunologist at Washington University in St. Louis, Missouri, who is working on two early-stage vaccines. One2 is based on a weakened livestock virus. The other3 is based on a chimpanzee adenovirus, like the Oxford–AstraZeneca effort.

Diamond’s adenovirus vaccine, unlike any of the leading candidates, is designed to be administered through the nose. A team led by Diamond and Washington University cancer biologist David Curiel found3 that mice given a single dose of the intranasal vaccine were fully protected from SARS-CoV-2, with virtually no sign of virus in their upper or lower airways. Mice that received an injection of the same vaccine were only partially protected, echoing animal data from some leading candidates. This was because the intranasal vaccine summoned potent ‘mucosal’ immune responses that can block the virus at the site of infection in the upper airways, the team says.

On the basis of such results, Diamond feels that his team has “a mission” to push its vaccines into human trials, to “see if they’re going to be one of the last ones standing — even if they’re not the first ones out there”. His university has completed a deal to license the intranasal vaccine to a manufacturer, but Diamond hasn’t yet found anyone to advance his team’s livestock-virus vaccine. Pharmaceutical company Merck is developing its own vaccine based on the same virus, which is also the backbone of the Ebola vaccine that the firm had approved in the United States and the European Union last year. Many companies “just don’t have the bandwidth, money, the wherewithal or desire to actually pick up additional platforms”, says Diamond. “The challenge has been to find partners.”

Funders’ priorities

Many of the vaccines gunning for the first approvals won early funding from CEPI, which has so far spent nearly US$900 million on nine COVID-19 candidates. US government agencies including the Biomedical Advanced Research and Development Authority (BARDA) have spent billions of dollars supporting a handful of candidates as part of Operation Warp Speed. But other funders, with their own priorities, are stepping in to help academics turn their experimental vaccines into products.

With many wealthy countries snapping up early supplies of the leading COVID-19 vaccine candidates, some of these teams have set their sights on developing vaccines for the rest of the world.

Neil King, a biochemist at the University of Washington in Seattle, and his team are readying a nanoparticle vaccine for clinical trials, with support from the Bill and Melinda Gates Foundation in Seattle. The effort, which King is leading with University of Washington structural biologist David Veesler, has produced a vaccine consisting of a self-assembling virus-like particle that is dotted with 60 copies of the receptor binding domain of the spike protein that SARS-CoV-2 uses to enter human cells. In a recent preprint, the team reported that tiny doses of the vaccine led to whopping immune responses in mice4.


The jab could be supplied to low- and middle-income countries, says King. It comprises ‘recombinant’ proteins made using DNA from multiple sources — which are already used as medical products including insulin, blood-clotting factors, and other vaccines, so there is huge global manufacturing capacity for them. ‘Virus-like particle’ vaccines that self-assemble from these proteins also have a strong track record: existing vaccines against human papillomavirus, a cause of cervical cancer, and hepatitis B are based on the technology. Clinical trials of the nanoparticle vaccine are set to begin in December. “We don’t have a billion dollars from BARDA, but we are moving the programme forward and making sure we don’t lose time,” says King.

And last month, Baylor College of Medicine in Houston, Texas, announced that it had nonexclusively licensed its protein-based COVID-19 vaccine candidate to an Indian manufacturer, Biological E in Hyderabad. The vaccine, which is estimated to cost around $2 per dose, could be used on its own or to boost the immune response elicited by other vaccines, says Baylor vaccine scientist Maria Elena Bottazzi, who is co-leading the effort to develop it. “While we wait for the Warp Speed vaccines to really show us the data, we need to start thinking about second-generation vaccines.”

Researchers say that funders need to step in to provide guidance and financial support for COVID-19 vaccines. But as much as underdog developers would like to see their vaccines help bring the pandemic to an end, they are still rooting for their better-funded competitors to succeed. “As a human being, my hope is that none of the candidates fail,” says King. “I want every single one of them to work, and I want this thing gone.”

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